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Analysis Of Common Somatic Mutations In Colorectal Carcinoma And Associated Dysregulated Pathwaysarts
Sobia Hassan1, Ambrina Khatoon2, Uzma Bukhari3
1Pathology Department,Ziauddin University, Karachi.
Background:
Identification of gene targets and biological pathways involved in colorectal carcinoma (CRC) is essential for better management of patients. Our study aims to highlight common somatic mutations in colorectal carcinoma and to identify dysregulated pathways and gene enrichment based on KRAS and BRAF interaction network analysis.
Methods:
By using cancer browser tool in COSMIC database, mutation frequencies of the top 20 mutated genes listed for colorectal adenocarcinoma were identified. The most frequent variants of selected genes were explored with ClinVar database which led to identification of protein change along with its cytogenic location, variant type, variant length and the associated single nucleotide polymorphism (SNP). These identified SNPs were searched in Pakistani database using 1000genome in an attempt to identify common polymorphisms. Using the database ClinicalTrial.gov the number of clinical trials based upon these selected mutations was explored. Enrichment and protein interaction (PI) analysis of KRAS and BRAF was carried out to reveal significant biological pathways associated with these genes.
Results:
In cumulative data, among all variants about 57% of substitution mutations are observed to be G>A including mutations in KRAS, Tp53, SMAD4, PI3K and NRAS. The mutations of KRAS (c.35G>A), TP53 (c.524G>A) and APC (c.4348C>T) were found to be pathogenic with single nucleotide variation and variant length of 1bp. Searching 1000genome database revealed that 100 % of alleles found in East Asian population studied are 'C'(frequency=1). Significant biological pathways (<0.05) identified by our search include Trk receptor signalling mediated by the MAPK pathway, signalling to p38 via RIT and RIN, signalling to ERKs, Frs2-mediated activation, ARMS-mediated activation and prolonged ERK activation events.
Conclusions:
Our study highlights the role of genetic profiling in CRC, with emphasis on mutations which may define treatment outcome. Targeting several collateral pathways simultaneously may be further explored to improve colorectal cancer therapeutics.
Insights
This study identifies common gene mutations in colorectal cancer (CRC) and reveals key biological pathways like MAPK signaling. Understanding these genetic alterations can improve CRC treatment strategies.
Area of Science:
- Oncology
- Genetics
- Bioinformatics
Background:
- Colorectal carcinoma (CRC) management requires identifying critical gene targets and biological pathways.
- Somatic mutations and their associated pathways are key to understanding CRC progression.
Purpose of the Study:
- To identify common somatic mutations in colorectal carcinoma.
- To analyze dysregulated pathways and gene enrichment using KRAS and BRAF interaction networks.
Main Methods:
- Utilized COSMIC and ClinVar databases to identify mutation frequencies and variant details.
- Analyzed single nucleotide polymorphisms (SNPs) in Pakistani and East Asian populations via the 1000 Genomes database.
- Performed enrichment and protein-interaction analysis for KRAS and BRAF to identify significant biological pathways.
Main Results:
- Observed 57% of substitution mutations as G>A, including in KRAS, TP53, SMAD4, PI3K, and NRAS.
- Identified pathogenic mutations in KRAS, TP53, and APC with single nucleotide variations.
- Revealed significant pathways including MAPK signaling, p38 signaling, and ERK activation.
Conclusions:
- Genetic profiling in CRC is crucial for defining treatment outcomes.
- Simultaneous targeting of multiple pathways shows potential for improving colorectal cancer therapeutics.
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